| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Giant Cell Arteritis (GCA) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Giant cell arteritis (GCA) is a condition in which medium and large arteries, usually in the head and neck, become inflamed. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10047116 |
| E.1.2 | Term | Vascular inflammations |
| E.1.2 | System Organ Class | 100000004866 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To investigate the efficacy of sirukumab (100 mg q2w for 12 months) as compared to placebo, each
administered in addition to a 6-month prednisone treatment regimen
|
|
| E.2.2 | Secondary objectives of the trial |
1. To assess cumulative prednisone doses in subjects treated with sirukumab plus prednisone as compared to placebo plus prednisone
2. To investigate the efficacy of Sirukumab (100 mg q2w for 12 months) with 3-month prednisone treatment versus placebo with a 6-month prednisone treatment
3. To investigate the efficacy of sirukumab (100 mg q2w for 12 months) with a 6-month prednisone treatment as compared to placebo with a 12-month prednisone treatment
4. To investigate the efficacy of sirukumab (100 mg q2w for 12 months) with a 3-month prednisone treatment versus placebo with a 12-month prednisone treatment
5. To investigate the efficacy of sirukumab (50 mg q4w for 12 months) as compared to placebo, each
administered in addition to a 6-month prednisone treatment
6. To investigate the efficacy of Sirukumab (50 mg q4w for 12 months) with a 6-month prednisone treatment as compared to placebo with a 12-month prednisone treatment |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A study to assess the utility of ultrasound imaging in monitoring disease activity in GCA in a cohort of subjects with new onset GCA.
Objectives:
1. To explore the utility of vascular ultrasound (US) imaging assessment of inflammation in temporal and axillary arteries as an indicator of disease activity in a cohort of study subjects.
2. To explore the predictive value of ultrasound for clinical efficacy GCA. |
|
| E.3 | Principal inclusion criteria |
1.Diagnosis of GCA defined by the following Revised GCA Diagnosis Criteria:
•Age ≥50 years.
•History of ESR ≥ 50 mm/hour or CRP ≥ 2.45 mg/dL (≥ 24.5 mg/L).
•Presence of at least one of the following:
oUnequivocal cranial symptoms of GCA (new onset localized headache, scalp or temporal artery tenderness, ischemia-related vision loss, or otherwise
unexplained mouth or jaw pain upon mastication).
oUnequivocal symptoms of PMR, defined as shoulder and/or hip girdle pain associated with inflammatory stiffness.
•Presence of at least one of the following:
oTemporal artery abnormality on biopsy revealing features of GCA.
oEvidence of large-vessel vasculitis by angiography or cross-sectional imaging, including but not limited to magnetic resonance angiography (MRA), computed tomography angiography (CTA), ultra sound (US) or positron emission
tomography-computed tomography (PET-CT).
oEvidence of temporal artery vasculitis on US (for US imaging qualified
centres only)
2.Active GCA within 6 weeks of Randomization (Baseline) where active disease is
defined by an ESR ≥ 30 mm/hr or CRP ≥ 1 mg/dL (≥ 10 mg/L) AND the presence of at least one of the following:
• Unequivocal cranial signs and symptoms of GCA (new onset localized headache, scalp or temporal artery tenderness, reduced or absent pulsation in temporal artery, stroke, scalp necrosis, pain over face/scalp arteries or otherwise unexplained mouth or jaw pain upon mastication [i.e., jaw claudication]).
• Visual signs and symptoms associated with GCA, including ischemia-related vision loss [permanent vision loss due to AION, amaurosis fugax, episodic blurry vision], diplopia, scotoma nerve palsies, relative afferent papillary defects, central retinal artery occlusions.
•Unequivocal symptoms of PMR, defined as shoulder and/or hip girdle pain associated with inflammatory stiffness.
•Other features judged by the clinician investigator to be consistent with GCA or PMR flares (i.e., new or worsened extremity claudication, fever of unknown
origin).
3.At screening, receiving prednisone treatment with a minimum dose of 20 mg/day for the treatment of active GCA. Subjects not currently receiving prednisone treatment must commence dosing (minimum 20 mg/day of prednisone) at the screening visit.
4.Clinically stable GCA disease at baseline such that the subject is able to safely participate in the blinded prednisone taper regimen in the opinion of the investigator.
5.Practicing acceptable methods of birth control as follows:
Males:
Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until 4 months after the last dose of study medication:
h. Vasectomy with documentation of azoospermia.
i. Male condom plus female partner use of one of the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Childbearing potential
Male subjects should also not donate sperm from the time of first dose of study medication until 4 months after the last dose of study medication.
Females:
Female subjects of child-bearing potential must use one of the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Childbearing potential
6.No evidence of active or latent infection with Mycobacterium tuberculosis (TB), as defined by all of the following:
•No history of active or latent TB infection.
•A negative diagnostic TB test at Screening defined as a negative QuantiFERON Gold test or T-spot test (performed locally) (NB: 2 successive indeterminate QuantiFERON tests will be considered as a positive result). In cases where an initial indeterminate QuantiFERON test result may be related to sample processing issues, the second QuantiFERON test may be performed at either the local laboratory or the central laboratory at the discretion of
the investigator. Re-testing is only permitted for indeterminate result. If the re-test also produces an indeterminate result, further re-testing to determine study eligibility is not permitted either at the local or central laboratory.
•Chest radiograph (both posterior-anterior and lateral views unless local guidelines recommend only a single view), taken within 12 weeks prior to baseline or at Screening, and read locally by a qualified radiologist, with no evidence of current active or previous inactive pulmonary tuberculosis.
NB: If there has been recent close contact with persons who have active TB prior to study enrolment the subject will be referred to a TB physician to undergo additional evaluation. |
|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1.Are pregnant or breastfeeding.
2.Recent (within the past 12 weeks) or planned major surgery that would impact on study procedures or assessments.
3.Organ transplantation recipients (except corneas within 3 months prior to baseline visit).
4.Had prior treatment with any of the following:
•Systemic immunosuppressives, including azathioprine, oral cyclosporine A,tacrolimus, mycophenolate mofetil, leflunomide, oral or parenteral gold, and IL-1ra (anakinra) within 4 weeks of baseline.
•Biologic agents targeted at reducing TNF (including but not limited to infliximab, golimumab, certolizumab pegol, etanercept, yisaipu, and adalimumab)within 4-8 weeks of baseline, depending on the agent*.
•Anti-IL6 (tocilizumab or any other anti-IL-6 agent) if:
-Used within 8 weeks of randomization
-Associated with a history of intolerance that precluded further treatment
A-ssociated with an inadequate response to 3 months of therapy
B-cell depleting agents (eg, rituximab) within 12 months prior to baseline or longer if B cell counts have not returned to normal range or baseline levelsCytotoxic drugs such as cyclophosphamide, chlorambucil, nitrogen mustard, or other alkylating agents within 4 weeks of baseline.
•Abatacept within 8 weeks of baseline.
•Tofacitinib within 4 weeks of baseline.
•Methotrexate use within 2 weeks of baseline.
•Methylprednisolone > 100 mg/day IV (or equivalent) within 8 weeks of baseline.
5.Regular or continuous systemic corticosteroid use for > 4 years.
6.Requires continued or repeated use of systemic corticosteroids for conditions other than GCA.
7.History of severe allergic reactions to monoclonal antibodies, human proteins, or excipients.
8.Evidence of serious concomitant disease, which in the opinion of the investigator makes them unsuitable for participation in the study.
9.Major ischemic event, unrelated to giant cell arteritis, within 12 weeks of screening.
10.Marked baseline prolongation of QTc interval>480 msec(QTcB or QTcF) or QTc>500 msec in subjects with Bundle Branch Block**, history of Torsade de Pointes, family history of long QT syndrome, history of second or third degree heart block.
**The QTc should be based on averaged QTc values of triplicate ECGs obtained over a brief (e.g., 5-10 minute) recording period.
11.Current liver disease that could interfere with the trial as determined by the physician investigator.
12.History of or current active diverticulitis, inflammatory bowel disease, or other symptomatic GI tract condition that might predispose to bowel perforation.
13.History of known demyelinating diseases such as multiple sclerosis or optic neuritis.
14.Active infections, or history of recurrent infections or have required management of acute or chronic infections, as follows:
•Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria,
•History or suspicion of chronic infection (e.g joint infection). OR
•Hospitalization for treatment of infection within 60 days of the baseline visit. OR
•Use of parenteral (IV or IM) antimicrobials (antibacterials, antivirals, antifungals, or antiparasitic agents) within 60 days of baseline or oral antimicrobials within 30 days of baseline.
15.Primary or secondary immunodeficiency.
16.HIV infection (positive serology for HIV antibody), hepatitis C (positive serology for hepatitis C antibody confirmed positive by hepatitis C RNA PCR which is reflexively performed).
17.Hepatitis B infection (positive test results for hepatitis B surface antigen or hepatitis
B core antibody).
18.Active malignancy or history of malignancy within previous 5 years (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured).
19.Laboratory abnormalities:
•AST or ALT >2.0 × upper limit of normal (ULN).
•Total bilirubin >ULN with the exception of Gilbert’s disease.
•Platelet count <140 × 109/L.
•Hemoglobin <8.5 g/dL.
•WBC count <3.5 × 109/L.
•ANC <2 × 109/L.
•ALC <0.5 × 109/L.
•Serum creatinine ≥2.0 mg/dL (SI: positive ≥177 μmol/L).
20.Has received, or is expected to receive, any live virus or bacterial vaccination within 3 months before the first administration of study drug, during the study, or within 4 months after the last administration of study drug.
21.Any other autoimmune disease (such as SLE, RA, inflammatory arthritis, other vasculitides, scleroderma, polymyositis, dermatomyositis or other similar systemic connective tissue diseases).
22.Uncontrolled psychiatric or emotional disorder, drug abuse, alcohol abuse within past 3 years.
*Please refer to the Study Procedures Manual (SPM) for guidance.
**If seropositive, consultation with a physician with expertise in the treatment of HIV or hepatitis B or C virus infection is recommended. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
•Proportion of subjects in sustained remission at Week 52
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Part A: 52-week double blind treatment phase
•Median and cumulative prednisone dose over time
•Proportion of subjects in sustained remission at each time point of assessment from week 12 to week 52
•Proportion of subjects in remission over time
•Time to first GCA flare after clinical remission
•Number of disease flares per patient over time
•Proportion of subjects requiring hospitalizations for disease flare and number of hospitalizations for disease flare
•Incidence of adverse events and serious adverse events, incidence of corticosteroid-related adverse events, changes in vital signs, hematology and
clinical chemistry parameters
•Patient and clinician reported outcomes including SF-36v2, EQ-5D (5L), FACITFatigue, Pain NRS, Steroid Impact PRO, HAQ-DI, PGIC, PtGA, PhGA
•Change from baseline in ESR over time
•Change from baseline in serum CRP over time
•Serum concentrations of sirukumab
•Serum anti-sirukumab antibodies
•Change from baseline in IFN-γ and IL-17A
•Change from baseline in serum markers of bone formation/resorption: CTX1/P1NP
•Correlation of genetic markers with the safety and efficacy response to sirukumab |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week -6, 0, 2, 4, then every 4 weeks to week 52 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 62 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Bulgaria |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| New Zealand |
| Poland |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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